The present invention is directed to self-preserved pharmaceutical compositions. More specifically, the invention is directed to the provision of aqueous, multi-dose pharmaceutical compositions that have been formulated so as to have sufficient antimicrobial activity to satisfy the preservation efficacy requirements of the United States Pharmacopeia (“USP”) and analogous guidelines in other countries, without requiring a conventional antimicrobial preservative, such as benzalkonium chloride, polyquaternium-1, hydrogen peroxide (e.g., sodium perborate), or chorine-containing agents. The ability to achieve self-preservation is based on a unique combination of formulation components and criteria.
Many pharmaceutical compositions are required to be sterile (i.e., free of bacteria, fungi and other pathogenic microorganisms). Examples of such compositions include: solutions and suspensions that are injected into the bodies of humans or other mammals; creams, lotions, solutions or other preparations that are topically applied to wounds, abrasions, burns, rashes, surgical incisions, or other conditions where the skin is not intact; and various types of compositions that are applied either directly to the eye (e.g., artificial tears, irrigating solutions, and drug products), or are applied to devices that will come into contact with the eye (e.g., contact lenses).
The foregoing types of compositions can be manufactured under sterile conditions via procedures that are well known to those skilled in the art. However, once the packaging for a product is opened, such that the composition contained therein is exposed to the atmosphere and other sources of potential microbial contamination (e.g., the hands of a human patient), the sterility of the product may be compromised. Such products are typically utilized multiple times by the patient, and are therefore frequently referred to as being of a “multi-dose” nature.
Due to the frequent, repeated exposure of multi-dose products to the risk of microbial contamination, it is necessary to employ a means for preventing such contamination from occurring. The means employed may be: (i) a chemical agent that prevents the proliferation of microbes in a composition, which is referred to herein as an “antimicrobial preservative”; or (ii) a packaging system that prevents or reduces the risk of microbes reaching a pharmaceutical composition within a container.
Prior multi-dose ophthalmic compositions have generally contained one or more antimicrobial preservations in order to prevent the proliferation of bacteria, fungi and other microbes. Such compositions may come into contact with the cornea either directly or indirectly. The cornea is particularly sensitive to exogenous chemical agents. Consequently, in order to minimize the potential for harmful effects on the cornea, it is preferable to use anti-microbial preservatives that are relatively non-toxic to the cornea, and to use such preservatives at the lowest possible concentrations (i.e., the minimum amounts required in order to perform their anti-microbial functions).
Balancing the anti-microbial efficacy and potential toxicological effects of anti-microbial preservatives is sometimes difficult to achieve. More specifically, the concentration of an antimicrobial agent necessary for the preservation of ophthalmic formulations from microbial contamination may create the potential for toxicological effects on the cornea and/or other ophthalmic tissues. Using lower concentrations of the anti-microbial agents generally helps to reduce the potential for such toxicological effects, but the lower concentrations may be insufficient to achieve the required level of biocidal efficacy (i.e., antimicrobial preservation).
The use of an inadequate level of antimicrobial preservation may create the potential for microbial contamination of the compositions and ophthalmic infections resulting from such contaminations. This is also a serious problem, since ophthalmic infections involving Pseudomonas aeruginosa or other virulent microorganisms can lead to loss of visual function or even loss of the eye.
Thus, there is a need for a means of enhancing the activity of anti-microbial agents so that very low concentrations of the agents can be utilized without increasing the potential for toxicological effects or subjecting patients to unacceptable risks of microbial contamination and resulting ophthalmic infections.
Ophthalmic compositions are generally formulated as isotonic, buffered solutions. One approach to enhancing the anti-microbial activity of such compositions is to include multi-functional components in the compositions. In addition to performing their primary functions, these multi-functional components also serve to enhance the overall anti-microbial activity of the compositions.
The following publications may be referred to for further background regarding the use of multi-functional components to enhance the antimicrobial activity of ophthalmic compositions:    1. U.S. Pat. No. 5,817,277 (Mowrey-McKee, et al; tromethamine);    2. U.S. Pat. No. 6,503,497 (Chowhan, et al.; borate/polyol complexes);    3. U.S. Pat. No. 5,741,817 (Chowhan, et al.; low molecular weight amino acids such as glycine);    4. U.S. Pat. No. 6,319,464 (Asgharian; low molecular weight amino alcohols); and    5. U.S. Patent Application Publication No. US 2002/0122831 A1 (Mowrey-McKee, et al.; bis-aminopolyols).
The present invention is also based in-part on a finding that zinc further enhances the antimicrobial activity of ophthalmic compositions containing borate/polyol complexes of the type described herein. The use of zinc to enhance the antimicrobial activity of pharmaceutical compositions, including ophthalmic solutions, is well known. See, for example, the following articles and patent publications, as well as U.S. Pat. No. 6,348,190 and JP 2003-104870, cited above:    McCarthy, “Metal Ions and Microbial Inhibitors”, Cosmetic & Toiletries, 100:69-72 (February 1985);    Zeelie, et al., “The Effects of Selected Metal Salts on the Microbial Activities of Agents used in the Pharmaceutical and Related Industries”, Metal Compounds in Environment and Life, 4:193-200 (1992);    Zeelie, et al., “Effects of Copper and Zinc Ions on the Germicidal Properties of Two Popular Pharmaceutical Antiseptic Agents, Cetylpyridinium Chloride and Povidone-iodine”, Analyst, 123:503-507 (March 1998);    McCarthy, et al., “The Effect of Zinc Ions on the Antimicrobial Activity of Selected Preservatives”, Journal of Pharmacy and Pharmacology, Vol. 41 (1989);    U.S. Pat. No. 6,482,799 (Tuśe, et al.);    U.S. Pat. No. 5,320,843 (Raheja, et al.);    U.S. Pat. No. 5,221,664 (Berkowitz, et al.);    U.S. Pat. No. 6,034,043 (Fujiwara, et al.);    U.S. Pat. No. 4,522,806 (Muhlemann, et al.);    U.S. Pat. No. 6,017,861 (Fujiwara, et al.); and    U.S. Pat. No. 6,121,315 (Nair, et al.).However, the use of zinc ions in combination with borate/polyol complexes, as described herein is not disclosed or suggested by the prior art.
The compositions of the present invention are multi-dose products that do not contain a conventional antimicrobial preservative (e.g., benzalkonium chloride), but yet are preserved from microbial contamination. Such compositions have been referred to in the art as being “preservative free” (see, e.g., U.S. Pat. No. 5,597,559 issued to Olejnik, et al.). Compositions that are preserved from microbial contamination as a result of the inherent antimicrobial activity of one or more components of the compositions are also referred to in the art as being “self-preserved” (see, e.g., U.S. Pat. No. 6,492,361 issued to Muller, et al.).
The following publication may be referred to for further background regarding pharmaceutical compositions that are “preservative-free” or “self-preserving”: Kabara, et al., Preservative-Free and Self-Preserving Cosmetics and Drugs—Principles and Practice, Chapter 1, pages 1-14, Marcel Dekker, Inc. (1997).
The multi-dose compositions of the present invention, which do not contain a conventional antimicrobial preservative are referred to herein as being “self-preserved”.